Radiolabeled Somatostatin Analogs-A Continuously Evolving Class of Radiopharmaceuticals

Simple Summary Somatostatin receptors (SSTs) are of particular interest in oncology because these proteins are overexpressed on the cell membranes of different human malignancies, especially neuroendocrine tumors (NETs) and neuroendocrine neoplasms (NENs). Radiolabeled short peptide analogs of the natural hormone somatostatin have been developed over the years to target SST-expressing tumors and are used for both imaging (diagnosis) and therapy. Today, this type of radiopharmaceutical plays a pivotal role in the management of NET and NEN patients. Despite their clinical success, new developments in recent years, in terms of peptide analogs and radionuclides, have shown certain advantages and hold promise for further improvement in both the diagnosis and therapy of SST-expressing tumors, even beyond NETs and NENs. Somatostatin receptors (SSTs) are recognized as favorable molecular targets in neuroendocrine tumors (NETs) and neuroendocrine neoplasms (NENs), with subtype 2 (SST2) being the predominantly and most frequently expressed. PET/CT imaging with Ga-68-labeled SST agonists, e.g., Ga-68-DOTA-TOC (SomaKit TOC(R)) or Ga-68-DOTA-TATE (NETSPOT(R)), plays an important role in staging and restaging these tumors and can identify patients who qualify and would potentially benefit from peptide receptor radionuclide therapy (PRRT) with the therapeutic counterparts Lu-177-DOTA-TOC or Lu-177-DOTA-TATE (Lutathera(R)). This is an important feature of SST targeting, as it allows a personalized treatment approach (theranostic approach). Today, new developments hold promise for enhancing diagnostic accuracy and therapeutic efficacy. Among them, the use of SST2 antagonists, such as JR11 and LM3, has shown certain advantages in improving image sensitivity and tumor radiation dose, and there is evidence that they may find application in other oncological indications beyond NETs and NENs. In addition, PRRT performed with more cytotoxic alpha-emitters, such as Ac-225, or beta(-) and Auger electrons, such as Tb-161, presents higher efficacy. It remains to be seen if any of these new developments will overpower the established radiolabeled SST analogs and PRRT with beta(-)-emitters.

Automated summary

Somatostatin receptors (SSTs) are highly expressed in neuroendocrine tumors and neuroendocrine neoplasms, making them favorable molecular targets. Radiolabeled SST agonists, such as Ga-68-DOTA-TOC and Ga-68-DOTA-TATE, are used for PET/CT imaging and play an important role in staging and restaging these tumors. New developments, including the use of SST2 antagonists and more cytotoxic radioisotopes, show promise in enhancing diagnostic accuracy and therapeutic efficacy for SST-expressing tumors. However, further research is needed to determine if these new developments can surpass the established radiolabeled SST analogs and beta(-)-emitter PRRT.